1. Field of Invention
This invention relates to novel oxadiazolyl imidazobenzodiazepine compounds pharmaceutical compositions thereof, method of treating therewith, and to methods of preparing such compounds. The novel compounds are useful in psychopharmaceutical applications, e.g., in the treatment of central nervous system ailments, for example, as an anticonvulsant or an anxiolytic.
2. Prior Art
It is well known (Squires, R. F. and Braestrup, C., Nature (London) 266, (1977) 734) that specific sites in the central nervous systems of vertebrates exhibit a high specific affinity for binding 1,4- and 1,5-benzodiazepines. These sites are called benzodiazepine receptors.
Ferrosan European patent application No. 109,921 (published May 30, 1984) and corresponding U.S. Pat. No. 4,507,313 (filed Nov. 15, 1983, issued Mar. 26, 1985) disclose compounds having the general Formula I ##STR2## wherein R' is hydrogen, chlorine, fluorine, or nitro in the 7- or 8-position.
R.sup.1 is hydrogen or lower-alkyl of up to 3 carbon atoms, PA1 R.sup.3 is an oxadiazolyl of the formula ##STR3## wherein R" is lower-alkyl of up to 3 carbon atoms, PA1 A . . . B is a grouping of the formula ##STR4## wherein R.sup.5 is hydrogen or methyl, and PA1 R"' is hydrogen or chlorine. PA1 R.sup.3 =H, CH.sub.3, and PA1 R.sup.4, R.sup.5 =H, halogen ##STR6## wherein X= ##STR7## wherein R.sup.1 =alkyl, cycloalkyl, CF.sub.3, or methoxymethyl PA1 R.sup.4, R.sup.5 =H, halogen, CF.sub.3, and PA1 n=2 or 3. PA1 X.dbd.CF.sub.3 --200.1.degree. C. PA1 X.dbd.CH.sub.3 --175.0.degree.-175.5.degree. C. PA1 X.dbd.CN--237.degree.-239.degree. C.
This U.S. Pat. No. 4,507,313 further discloses (Column 1, lines 59 through Column 2, line 4) that such oxadiazolyl benzodiazepines of EP No. 27,214 (U.S. Pat. No. 4,316,839) column 4, line 2 and oxadiazolyl beta-carbolines, as disclosed in earlier European patent application 54,507 (U.S. Pat. No. 4,435,403), exhibit stronger binding affinity for the benzodiazepine receptors than the analogous substituted compounds which are alkyl esters (rather than such oxadiazolyl derivatives). Roche European patent application No. 150,040 (published July 31, 1985) and corresponding Danish patent application 245/85 (made available July 22, 1984) and the presumed corresponding U.S. patent application also disclose oxadiazolyl imidazobenzodiazepines.
The disclosure of Roche European patent application No. 150,040 is very broad. Its disclosure of 1,2,4-oxadiazolyl-benzodiazepine compounds can be illustrated by Formulas II and III. ##STR5## wherein R.sup.1 =alkyl, cycloalkyl, methoxymethyl
This Roche European patent application Nr. 150,040 includes no examples of compounds having the formula IV. ##STR8## wherein R.sup.3 is ##STR9## and much less wherein R.sup.3 is ##STR10## nor does this application disclose compounds of above formula IV wherein any of R.sup.4 or R.sup.5 is cyano, lower alkyl, or trifluoromethyl and further no compounds wherein R.sup.4 is F, cyano, lower alkyl, or trifluoromethyl and of course much less compounds of formula IV wherein R.sup.3 is ##STR11## and R.sup.4 is F, CF.sub.3, CH.sub.3, or CN.
The compounds of Roche EP No. 150,040 examples 2, 3, 16, and 43 are old compounds of Ferrosan U.S. Pat. No. 4,507,313 column 2, lines 5-6, and examples 2 and 3 are preferred compounds of Roche EP No. 150,040 page 5 lines 34-37.
The compounds of Roche EP No. 150,040 examples 2, 3, 16, 29, 32, 43, 44, 45, 49, 50, 51, 52, 53, and 56 are 5,6-dihydro-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine compounds. (Compounds according to above formula II).
The compounds of Roche EP No. 150,040 examples 1, 8, 9, 17, 18, 23, 30 are 10,11,12,12a-tetrahydro-9-oxo-9H-imidazo[1,5-a]azeto[2,1-c][1,4]benzodiaze pine compounds. (Compounds according to above formula III).
The compounds of Roche EP No. 150,040 examples 4, 5, 6, 7, 10, 11, 12, 13, 14, 15, 19, 20, 21, 22, 24, 25, 26, 27, 28, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 46, 48, 54, 55, 57, 58 and 59 are 11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodia zepine compounds. (Compounds according to above formula III).
The compound of Roche EP No. 150,040 example 47 is an 11,13a-dihydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine compound.
The compounds of Roche EP 150,040 examples 11, 15, 26, and 40 are 1,2,4-oxadiazol-3-yl compounds. (Compounds according to above formula III)
The compounds of Roche EP 150,040 examples 11, 15, 26, and 40 are 1,2,4-oxadiazol-3-yl compounds combined with an 11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodia zepine skeleton.
The compound of Roche EP No. 150,040 Example 40 is a 5-cyclopropyl-1,2,4-oxadiazol-3-yl compound with an 11,12,13,13a-tetrahydro-9-oxo-9H-imidazol[1,5-a]pyrrolo[2,1-c][1,4]benzood iazepine skeleton.
The compound of Roche EP No. 150,040 Example 40 is a 5-cyclopropyl-1,2,4-oxadiazol-3-yl compound which has been found grossly inferior in pharmacological and biochemical evaluations as further reported hereinafter.
Roche European patent application 150,040 further claims a process for the preparation of such compounds (II and III) by reacting compounds of Formula V and VI ##STR12## wherein R.sup.4, R.sup.5 and n have the meanings set forth in the foregoing and Y is a leaving group, with a compound of the formula EQU CN--CH.sub.2 --X
wherein x has the meaning set forth in the foregoing for Formula III.
All oxadiazoles in the Roche application are actually made by reacting intermediates V or VI with CN--CH.sub.2 --CO.sub.2 R to form a compound of Formula II or III having the --CO.sub.2 R substituent instead of an oxadiazole ring, which compound is thereafter, in several steps, converted to an oxadiazole.
The new compounds provided by the present invention have the same type of structure and activity as disclosed in the prior art, but the particular and specific compounds of the present invention, and the particular and specific "subject matter as a whole", including not only their chemical structure but also their pharmacological properties, have been found to be both advantageous and unobvious from the standpoint of one skilled in the art.